Rationale for Surrogate Endpoints and Conditional Marketing Authorization of New Therapies for Kidney Transplantation

Naesens, Maarten; Loupy, Alexandre; Hilbrands, Luuk B.; Oberbauer, Rainer; Bellini, Maria Irene; Glotz, Denis; Grinyó, Josep M.; Heemann, Uwe; Jochmans, Ina; Pengel, Liset; Reinders, Marlies E.J.; Schneeberger, Stefan; Budde, Klemens

doi:10.3389/ti.2022.10137

Cited by 10 publications

(8 citation statements)

References 64 publications

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“…As it is now being more frequently recognized that more treatment options are necessary to further improve graft outcomes, novel approaches would increase the ability to perform trials aiming to test these treatment options are needed. 22 The absence of a control group in a single-arm trial means not only lower overall costs of conducting such trials but also a lower number of KTRs who would need to be enrolled, thus increasing the number of phase II trials that could be conducted in search of new potential treatments for further clinical testing. 23 The sample size and power calculation for the RIMINI study were based on the published data from the large OSAKA study.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus After rATG and Infliximab Induction Immunosuppression—RIMINI Trial

et al. 2023

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Background. Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation. Methods. This is a phase II international multicenter open-label single-arm confidence interval (CI)–based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established. Results. Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P = 0.039) were observed in the study cohort. Conclusions. A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).

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Section: Discussionmentioning

confidence: 99%

Tacrolimus After rATG and Infliximab Induction Immunosuppression—RIMINI Trial

et al. 2023

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“…Another approach could be to not solely rely on BPAR as a predictor of long-term graft outcome but to consider the heterogeneity in the causes of graft failure. 25 Quantitative metrics based on the mechanisms of graft injury (eg, rejection type, BK nephropathy, nephrotoxicity) could be developed and validated. In December 2022, the European Medicines Agency qualified the iBOX as a secondary endpoint prognostic for death-censored allograft loss in kidney transplant recipients to be used in clinical trials to support the evaluation of novel immunosuppressive therapy applications.…”

Section: Bela] and Tacrolimus [Tac] Extended Release [Envarsus Xr And...mentioning

confidence: 99%

Acute Rejection After Kidney Transplant—An Endpoint Not Predictive of Treatment Effect on Graft Survival

Fitzsimmons

Naesens

2023

Transplantation

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“…Definitions of all-cause and overall graft failure are discussed elsewhere in this Special Issue ( 2 ); of note, in this document, “graft failure” denotes loss of graft function, not overall graft failure (which includes patient death as a reason for graft failure). Given that late graft failure (excluding death with a functioning graft) is often multifactorial ( 4 ), it is difficult to predict such failure accurately with a single marker; a composite marker may more fully reflect the heterogeneity.…”

Section: Definition and Causes Of Graft Failurementioning

confidence: 99%

“…If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes [see Naesens et al, this issue ( 2 )], then the surrogate endpoint for graft failure (i.e., loss of graft function; excluding death with a functioning graft) for use in RCT needs clearer definition. A good surrogate endpoint should fulfill four criteria: 1) The disease process is sufficiently understood; 2) The surrogate endpoint has biologic plausibility; 3) The strength of the consistency supports the relationship between the surrogate marker and outcome; 4) Treatment effects on the surrogate endpoint predict treatment effects on the clinical outcome of interest ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…A good surrogate endpoint should fulfill four criteria: 1) The disease process is sufficiently understood; 2) The surrogate endpoint has biologic plausibility; 3) The strength of the consistency supports the relationship between the surrogate marker and outcome; 4) Treatment effects on the surrogate endpoint predict treatment effects on the clinical outcome of interest ( Table 1 ). In addition, the acceptability of a surrogate endpoint for conditional marketing authorization of new therapies also depends on a benefit–risk evaluation and/or public health aspects, such as a serious life-threatening disease with no other therapeutic option, difficulties with studying the (rare or delayed) clinical endpoint, and the availability of a large safety database ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Surrogate Endpoints for Late Kidney Transplantation Failure

Naesens¹,

Budde

Hilbrands³

et al. 2022

Transpl Int

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In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.

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Rationale for Surrogate Endpoints and Conditional Marketing Authorization of New Therapies for Kidney Transplantation

Cited by 10 publications

References 64 publications

Tacrolimus After rATG and Infliximab Induction Immunosuppression—RIMINI Trial

Tacrolimus After rATG and Infliximab Induction Immunosuppression—RIMINI Trial

Acute Rejection After Kidney Transplant—An Endpoint Not Predictive of Treatment Effect on Graft Survival

Surrogate Endpoints for Late Kidney Transplantation Failure

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